Multiple Roles for Sphingolipids in Steroid Hormone Biosynthesis

Lucki, Natasha C.; Sewer, Marion B.

doi:10.1007/978-1-4020-8831-5_15

Cited by 49 publications

(52 citation statements)

References 163 publications

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“…A growing body of literature supports the role of sphingolipid metabolism in the regulation of steroid hormone production (42). Our group has previously identified the role of SPH as an antagonist for SF-1 (75).…”

Section: Discussionmentioning

confidence: 87%

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Lucki

Bandyopadhyay

et al. 2012

Molecular and Cellular Biology

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Adrenocorticotropin (ACTH) signaling increases glucocorticoid production by promoting the interaction of transcription factors and coactivator proteins with the promoter of steroidogenic genes. The nuclear receptor steroidogenic factor 1 (SF-1) is essential for steroidogenic gene transcription. Sphingosine (SPH) is a ligand for SF-1. Moreover, suppression of expression of acid ceramidase (ASAH1), an enzyme that produces SPH, increases the transcription of multiple steroidogenic genes. Given that SF-1 is a nuclear protein, we sought to define the molecular mechanisms by which ASAH1 regulates SF-1 function. We show that ASAH1 is localized in the nuclei of H295R adrenocortical cells and that cyclic AMP (cAMP) signaling promotes nuclear sphingolipid metabolism in an ASAH1-dependent manner. ASAH1 suppresses SF-1 activity by directly interacting with the receptor. Chromatin immunoprecipitation (ChIP) assays revealed that ASAH1 is recruited to the promoter of various SF-1 target genes and that ASAH1 and SF-1 colocalize on the same promoter region of the CYP17A1 and steroidogenic acute regulatory protein (StAR) genes. Taken together, these results demonstrate that ASAH1 is a novel coregulatory protein that represses SF-1 function by directly binding to the receptor on SF-1 target gene promoters and identify a key role for nuclear lipid metabolism in regulating gene transcription.

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Section: Discussionmentioning

confidence: 87%

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Lucki

Bandyopadhyay

et al. 2012

Molecular and Cellular Biology

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“…Cluster II consisted mainly of genes responsible for steroid and lipid processing (Table S4). Of note was the prevalence of prostaglandin and lipid modifying enzymes in this cluster because these processes often provide ligands for PPARγ (28) as well as enrichment of sphingomyelin-and ceramide-related genes, which are strongly associated with lipid and steroid homeostasis (29,30).…”

Section: Resultsmentioning

confidence: 99%

Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy

Krause

Harris

Green

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

103

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Human mesenchymal stem cells (hMSCs) from bone marrow are regarded as putative osteoblast progenitors in vivo and differentiate into osteoblasts in vitro. Positive signaling by the canonical wingless (Wnt) pathway is critical for the differentiation of MSCs into osteoblasts. In contrast, activation of the peroxisome proliferator-activated receptor-γ (PPARγ)-mediated pathway results in adipogenesis. We therefore compared the effect of glycogen-synthetase-kinase-3β (GSK3β) inhibitors and PPARγ inhibitors on osteogenesis by hMSCs. Both compounds altered the intracellular distribution of β-catenin and GSK3β in a manner consistent with activation of Wnt signaling. With osteogenic supplements, the GSK3β inhibitor 6-bromo-indirubin-3′-oxime (BIO) and the PPARγ inhibitor GW9662 (GW) enhanced early osteogenic markers, alkaline phosphatase (ALP), and osteoprotegerin (OPG) by hMSCs and transcriptome analysis demonstrated up-regulation of genes encoding bone-related structural proteins. At higher doses of the inhibitors, ALP levels were attenuated, but dexamethasone-induced biomineralization was accelerated. When hMSCs were pretreated with BIO or GW and implanted into experimentally induced nonself healing calvarial defects, GW treatment substantially increased the capacity of the cells to repair the bone lesion, whereas BIO treatment had no significant effect. Further investigation indicated that unlike GW, BIO induced cell cycle inhibition in vitro. Furthermore, we found that GW treatment significantly reduced expression of chemokines that may exacerbate neutrophil-and macrophagemediated cell rejection. These data suggest that use of PPARγ inhibitors during the preparation of hMSCs may enhance the capacity of the cells for osteogenic cytotherapy, whereas adenine analogs such as BIO can adversely affect the viability of hMSC preparations in vitro and in vivo.osteogenesis | bone repair | tissue engineering

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“…For instance, vitamin D can control formation of S1P as described above, but S1P has also been shown to function as a messenger to control steroid hormone biosynthesis. 43,44 The detection of differences in metabolites matched to terpenes emphasizes this point. Terpenes are precursors to vitamin D, mitochondrial ubiquinol, cholesterol, and steroid hormones.…”

Section: Discussionmentioning

confidence: 99%

Metabolome-Wide Association Study of Primary Open Angle Glaucoma

Burgess

Uppal

Walker

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To determine if primary open-angle glaucoma (POAG) patients can be differentiated from controls based on metabolic characteristics. METHODS.We used ultra-high resolution mass spectrometry with C18 liquid chromatography for metabolomic analysis on frozen plasma samples from 72 POAG patients and 72 controls. Metabolome-wide Spearman correlation was performed to select differentially expressed metabolites (DEM) correlated with POAG. We corrected P values for multiple testing using Benjamini and Hochberg false discovery rate (FDR). Hierarchical cluster analysis (HCA) was used to depict the relationship between participants and DEM. Differentially expressed metabolites were matched to the METLIN metabolomics database; both DEM and metabolites significantly correlating with DEM were analyzed using MetaboAnalyst to identify metabolic pathways altered in POAG.RESULTS. Of the 2440 m/z (mass/charge) features recovered after filtering, 41 differed between POAG cases and controls at FDR ¼ 0.05. Hierarchical cluster analysis revealed these DEM to associate into eight clusters; three of these clusters contained the majority of the DEM and included palmitoylcarnitine, hydroxyergocalciferol, and high-resolution METLIN matches to sphingolipids, other vitamin D-related metabolites, and terpenes. MetaboAnalyst also indicated likely alteration in steroid biosynthesis pathways.CONCLUSIONS. Global ultrahigh resolution metabolomics emphasized the importance of altered lipid metabolism in POAG. The results suggest specific metabolic processes, such as those involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors, may contribute to POAG status and merit more detailed study with targeted methods.

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Multiple Roles for Sphingolipids in Steroid Hormone Biosynthesis

Cited by 49 publications

References 163 publications

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Acid Ceramidase (ASAH1) Represses Steroidogenic Factor 1-Dependent Gene Transcription in H295R Human Adrenocortical Cells by Binding to the Receptor

Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy

Metabolome-Wide Association Study of Primary Open Angle Glaucoma

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